Callum Kaye

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

BACKGROUND: The nature of multiple organ dysfunction syndrome (MODS) after traumatic injury is evolving as resuscitation practices advance and more patients survive their injuries to reach critical care. The aim of this study was to characterize contemporary MODS subtypes in trauma critical care at a population level. METHODS: Adult patients admitted to major trauma centre critical care units were enrolled in this 4-week point-prevalence study. MODS was defined by a daily total Sequential Organ Failure Assessment (SOFA) score of more than 5. Hierarchical clustering of SOFA scores over time was used to identify MODS subtypes. RESULTS: Some 440 patients were enrolled, of whom 245 (55·7 per cent) developed MODS. MODS carried a high mortality rate (22·0 per cent versus 0·5 per cent in those without MODS; P < 0·001) and 24·0 per cent of deaths occurred within the first 48 h after injury. Three patterns of MODS were identified, all present on admission. Cluster 1 MODS resolved early with a median time to recovery of 4 days and a mortality rate of 14·4 per cent. Cluster 2 had a delayed recovery (median 13 days) and a mortality rate of 35 per cent. Cluster 3 had a prolonged recovery (median 25 days) and high associated mortality rate of 46 per cent. Multivariable analysis revealed distinct clinical associations for each form of MODS; 24-hour crystalloid administration was associated strongly with cluster 1 (P = 0·009), traumatic brain injury with cluster 2 (P = 0·002) and admission shock severity with cluster 3 (P = 0·003). CONCLUSION: Contemporary MODS has at least three distinct types based on patterns of severity and recovery. Further characterization of MODS subtypes and their underlying pathophysiology may lead to future opportunities for early stratification and targeted interventions.

<h2>Abstract</h2><h3>Background</h3> Coronavirus disease 2019 (COVID-19) can lead to significant respiratory failure with between 14% and 18% of hospitalised patients requiring critical care admission. This study describes the impact of socioeconomic deprivation on 30-day survival following critical care admission for COVID-19, and the impact of the COVID-19 pandemic on critical care capacity in Scotland. <h3>Methods</h3> This cohort study used linked national hospital records including ICU, virology testing and national death records to identify and describe patients with COVID-19 admitted to critical care units in Scotland. Multivariable logistic regression was used to assess the impact of deprivation on 30-day mortality. Critical care capacity was described by reporting the percentage of baseline ICU bed utilisation required. <h3>Findings</h3> There were 735 patients with COVID-19 admitted to critical care units across Scotland from 1/3/2020 to 20/6/2020. There was a higher proportion of patients from more deprived areas, with 183 admissions (24.9%) from the most deprived quintile and 100 (13.6%) from the least deprived quintile. Overall, 30-day mortality was 34.8%. After adjusting for age, sex and ethnicity, mortality was significantly higher in patients from the most deprived quintile (OR 1.97, 95%CI 1.13, 3.41, <i>p</i>=0.016). ICUs serving populations with higher levels of deprivation spent a greater amount of time over their baseline ICU bed capacity. <h3>Interpretation</h3> Patients with COVID-19 living in areas with greatest socioeconomic deprivation had a higher frequency of critical care admission and a higher adjusted 30-day mortality. ICUs in health boards with higher levels of socioeconomic deprivation had both higher peak occupancy and longer duration of occupancy over normal maximum capacity. <h3>Funding</h3> None.